tbuckley/cabot-search huggingface dataset:
Abstract 10050: Omecamtiv Mecarbil and Its Effects on Cardiac Parameters in Heart Failure With Reduced Ejection Fraction (HFrEF). A Meta-Analysis of Randomized Controlled Trials
Authors: Arafat Farooqui, Haris Bilal, Naira Saleem, Syed Mohammad Mazhar Uddin, Sanjay Maheshwari, VIJAY SHETTY, Gerald Hollander, Jacob Shani
Journal: Circulation (2022)

Introduction: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator that has been shown to improve cardiac function in patients with HFrEF. Proposed mechanism of action suggests that it increases myocardial systolic function and systolic ejection time without associated increases in intracellular concentrations of calcium or the rate of change in left ventricular pressure or any direct effects on vascular tissue, cardiovascular receptors, or ion channels. Methods: Systematic review identified phase II/III randomized controlled trials (RCTs) evaluating OM versus placebo. Mean Difference (MD) of different echocardiographic parameters from baseline and Odds Ratios (OR) of cardiovascular (CV) death (along with 95% confidence intervals; CI) were extracted to compute pooled MD and OR using RevMan v.5.3. Random effects model was employed when there was significant heterogeneity (&gt;40%, as assessed by I-squared). Results: Four RCTs were finalized (n=9331; OM: 4722, placebo: 4609). Majority of the patients were males (n=7359; 79%), of white ethnicity (n=7345; 78.7%), and had ischemic heart failure (n=5109; 54.7%). All patients had EF &lt;40% and were on guideline-directed therapy. When patients were pooled for stroke volume; OM increased mean SV to 4.34 ml from baseline as compared to placebo (MD 4.34, 95% CI 2.03-6.65; p=0.0002; I 2 =0%). Mean LV ejection time increased to 32 milliseconds (ms) (MD 32.60, 27.34-37.87; p&lt;0.00001; I 2 =84%). OM resulted in 1.68 mm reduction in mean LV end-systolic diameter (MD -1.68; -2.73 to -0.62; p=0.002; I 2 =0%)). However, reduction in mean end-diastolic diameter (MD -1.05; -1.98 to -0.12; p=0.34; I 2 =42%) was statistically non-significant. Mean LV Fractional Shortening improved to 2% with OM but was statistically insignificant (MD 2.18; 0.54-3.82; p=0.09; I 2 =42%). OM resulted in slightly decreased heart rate (MD -1.77 beats/min; -2.29 to -1.24; p&lt;0.00001; I 2 =0%) with no effect on mean systolic BP (MD -0.05; -0.73 to 0.64; p=0.89; I 2 =0%). In terms of CV mortality, OM decreased the odds for mortality but results were statistically non-significant (OR 0.93, 95% CI 0.80 to 1.08; p=0.34; I 2 = 0%). Conclusion: Omecamtiv mecarbil improved the echocardiographic parameters in patients with HFrEF.
Abstract 10774: An Ambulatory Syncope Service is a Safe Pathway to Reduce Hospital Admissions
Authors: Brian X Wang, Rohin Reddy, Balaji Gothandaraman
Journal: Circulation (2022)

Introduction: Syncope affects up to 50% of people during a lifetime and is a common presentation to Emergency Departments (EDs). The Ambulatory Emergency Care Unit (AECU) Syncope pathway was established at our institution as a route by which low-risk patients presenting with syncope can undergo investigations without requiring hospital admissions as well as reducing length of stay for patients awaiting cardiology input. Hypothesis: The AECU Syncope pathway at Northwick Park Hospital, London, UK is safe and effective in reducing hospital admissions. Methods: We conducted a retrospective study of patients seen via the AECU Syncope pathway in 2020. These were referrals from the Emergency Department, General Practice and Inpatient departments for 24-hour tapes and echocardiograms. Results: A total of 221 patients were referred to the AECU syncope pathway in 2020. Of these, 36 patients (16%) had abnormalities on 24-hour tape. The majority were ectopics (n=12) but patients were also found to have arrhythmias (n=10), bradycardia (n=8) and heart block (n=6). 10 patients had aortic valve dysfunction identified on echocardiogram: 4 had severe aortic stenosis and the rest had milder classifications of aortic valve dysfunction. In total, 42 of the 221 patients had an abnormality on echocardiogram and/or 24-hour tape. Of these 42 patients, 14 were discharged as their abnormalities were insignificant for further cardiology input. 28 were referred to cardiology clinic for review as an outpatient. In terms of readmissions, 6 patients had readmissions within 30 days but only 1 patient had a readmission attributed to syncope, and this was a presyncope episode for which the patient was safety netted for during the previous admission. There were no deaths reported within 30 days of presentation. Within 1 year, there were 2 deaths, but neither were attributed to a major adverse cardiovascular event. Conclusions: The AECU syncope pathway presents a viable, efficient and safe route by which low-risk patients who are under investigation for a presumed syncopal episode can receive cardiology input without requiring a prolonged hospital admission. In doing so, there is a significant benefit to hospitals by reducing strain on bed space and staffing, thereby improving patient flow.
Abstract 10174: Intravenous Muse Cell Transplantation Enhances Angiogenesis and Reduces Muscle Fibrosis in a Mouse Hindlimb Ischemia Model
Authors: Yusuke Hori, Tomoya Kitani, Kenji Yanishi, TAKAOMI SUGA, Tetsuro Kusaba, Yoshihiro Kushida, Mari Dezawa, Satoaki Matoba
Journal: Circulation (2022)

Introduction: Multilineage-differentiating stress enduring (Muse) cells, a unique subpopulation of mesenchymal stem cells (MSCs), have been proposed as a promising cell source for regenerative medicine. However, the therapeutic potential of the Muse cells in ischemic limb disease remains unclear. In this study, we aimed to investigate therapeutic potential of Muse cell transplantation for the treatment of severe limb ischemia. Methods and Results: Muse cells isolated from human MSCs, non-Muse MSCs, or mouse bone marrow-derived mononuclear cells (BM-MNCs) were administered intravenously or intramuscularly to a mouse model of hindlimb ischemia (HLI). When the same number of cells were administered, blood flow recovery of the ischemic limb was significantly enhanced in the mice administered with Muse cells over 2 weeks compared to the others. Intravenous Muse cell administration resulted in comparable blood flow recovery to intramuscular Muse cell administration. Immunohistochemistry analysis revealed that intravenous Muse cell administration increased microvascular density and ameliorated interstitial fibrosis in the ischemic limb. We detected mCherry-labeled Muse cells expressing CD31 and human genomic DNA in the ischemic limb 1 week after the intravenous Muse cell administration. Muse cells produced higher VEGF compared to non-Muse MSCs, and Muse cell administration increased tissue VEGF level and expression of angiogenesis-related genes in the ischemic limb. Moreover, we found that Muse cell administration increased M2 macrophage and gene expression ratio of anti-inflammatory genes to proinflammatory gene, iNOS, in the ischemic limb. Lastly, we administered Muse cell intravenously at day 1 and 3, or high-dose BM-MNCs intramuscularly at day1 after the HLI surgery and found that repetitive Muse cell administration resulted in significantly enhanced blood flow recovery in the ischemic limb compared to high-dose BM-MNCs administration. Conclusions: Using an animal model, we demonstrated that intravenous Muse cell transplantation exerts robust therapeutic effects on limb ischemia injury. Therefore, Muse cell-based therapy may provide a novel therapeutic approach for patients with severe limb ischemia.
Abstract 11036: Aortic Valve Calcification is Associated With an Increased Risk of Mortality in Patients With Low Flow Low Gradient Moderate Aortic Stenosis
Authors: Nils Sofus Borg Mogensen, Rasmus Carter-Storch, Mohamed-salah Annabi, Jasmine Grenier-Delaney, Jacob Moller, Kristian Altern Ovrehus, Philippe Pibarot, Jordi Sanchez Dahl, Marie-Annick A Clavel
Journal: Circulation (2022)

Introduction: Aortic Valve Calcification (AVC) measured by computed tomography (C-CT) and Dobutamine stress echocardiography (DSE) are both important when determining AS severity in low flow low gradient (LFLG) AS. It is generally accepted that AS is moderate if aortic mean gradient is &lt;40mmHg on DSE and AVC is not severe. However, recent studies suggest that patients with moderate AS may have a worse outcome than expected when treated medically. Objective: To examine the correlation between AVC and mortality in patients with LFLG moderate AS on both DSE and C-CT when treated medically. Method: 88 Patients with LFLG AS (aortic mean gradient &lt;40 mmHg, aortic valve area &lt;1.0 cm 2 &amp; stroke volume index (SVi) &lt;35ml/m 2 ) and moderate AS on DSE and C-CT were identified from two prospective studies. AVC ratio was calculated as AVC divided by the sex-specific AVC threshold for severity; 2000 AU in males and 1200 AU in females. Results: Optimal threshold of AVC ratio to predict 2-year mortality was 0.68 on ROC-curve (AUC=0.72).Patients were stratified according to AVC ratio: 51 (58%) presented with AVC ratio &lt;0.7 and 37 (42%) with AVC ratio 0.7–1.0. 2 year survival was lower in the latter group (79.5±0.1 vs 46.9±0.1% - Figure 1). Age (78±9 vs 75±11, p=0.32), sex distribution (females 33 vs 41%, p=0.49) and DSE SVi increase (18±24 vs 18±12%, p=0.94) were similar in both groups. Patients with AVC ratio &lt;0.7 presented with higher LVEF (50±15 vs 44±15%, p=0.08) and lower aortic mean gradient at rest (20±7 vs 23±6 mmHg, p=0.01) and during DSE (21±14 vs 29±15 mmHg, p=0.03). In univariate Cox regression AVC ratio &gt;0.7 was associated with mortality: HR 2.91 [1.43-5.9], p=0.003. AVC ratio &gt;0.7 remained associated with mortality after adjustment for LVEF, aortic mean gradient, age and sex: HR 2.66 [1.24-5.7], p=0.012. Especially in patients with reduced LVEF: HR 3.47 [1.49-8.09], p=0.004. Conclusion: In patients with LFLG moderate AS an AVC ratio &gt; 0.7 is associated with increased risk of mid-term mortality.
Abstract 10542: The Utility of Repeat Coronary Angiography in Patients With Non Ischemic Cardiomyopathy
Authors: Ahmed Elkhapery, Hemanth Krishna Boppana, Mahmoud Eisa, Swati Chand, Mohamed Salah Mohamed, Deeptanshu Jain, Anas Hashem, Syed Faiz Abbas, Amr Mohamed, bipul baibhav
Journal: Circulation (2022)

Introduction: Up to 20% of angiograms reveal no coronary artery disease (CAD). Repeat studies are often done for chest pain, dyspnea, or reduction in ejection fraction (EF), but little is known about the diagnostic yield of this practice. Methods: Retrospective cohort of patients with no or minimal CAD on their first angiography (&lt;30% stenosis) and a repeat angiography in the last 5 years were included in the study. Results: There were 17 patients with no CAD and 26 patients with mild CAD on initial angiography, with 58 incidences of repeat angiography over an average follow-up of 5.4 years. The average time between procedures was 3.07 ± 1.83 years. Of these, 13 (30.2%) patients had demonstratable progression of CAD, and 8 (18.6%) patients ultimately required PCI. Findings on initial angiogram were associated with CAD progression (p=0.01) but not with intervention requirement (p=0.18), with the odds of new CAD in those with normal coronaries on first angiogram 0.07 (95% C.I. 0.008-0.634, p=0.005). Neither a low EF (&lt;50%) (n=21) nor a drop in EF by &gt;10% (n=17) was associated with CAD progression or PCI. The 8 patients that required PCI presented with STEMI (n=3), NSTEMI (n=3), and unstable angina (n=2). Only one patient with normal coronaries on initial angiography required PCI, after presenting with a STEMI 4 years later and found to have distal LAD thrombotic occlusion with otherwise no coronary atherosclerosis. Conclusions: Repeat angiography had a low yield in our patient population. A drop in EF by &gt;10% was not associated with new findings on repeat angiography or revascularization. Larger studies are needed to investigate if a drop in EF requires invasive testing.
Abstract 10918: Sex Differences in the Association of Triglyceride Glucose Index in Patients With Obstructive Coronary Artery Disease
Authors: Ya Wen Lu, Chuan Tsai Tsai, Ruey-Hsing Chou, Po-Hsun Huang
Journal: Circulation (2022)

Background: Insulin resistance is associated with cardiovascular disease due to direct or associated risk factors. We aimed to investigate the association of the Triglyceride glucose (TyG) index, as the surrogate marker of insulin resistance and obstructive coronary artery disease (CAD) between sex, especially for patients without diabetes. Methods: Patients with stable angina pectoris requiring invasive coronary angiography were enrolled, and they were divided into two groups according to the TyG index (ln[triglyceride x fasting plasma glucose]/2). Obstructive CAD was defined according to invasive coronary angiography results. Results: Patients with a higher TyG index (TyG index≧8.60) were associated with higher BMI, the prevalence of hypertension (HTN), diabetes mellitus (DM), and abnormal lipid profile compared with lower TyG index (TyG index &lt; 8.60). In women without diabetes, higher TyG index patients had a greater prevalence of obstructive CAD than the lower TyG index group (19.5% vs. 37.7%, p-value: 0.011). There was no difference in the majority of obstructive CAD in male patients between lower and higher TyG index. In multivariate logistic regression analysis, a higher TyG index remained the independent association of obstructive CAD only in women without diabetes (adjusted odds ratio (OR): 2.568, 95% CI: 1.238-5.327, p= 0.011) but not in the DM group. Conclusion: Higher TyG index, a marker of insulin resistance, was significantly related to a higher risk of obstructive CAD with gender disparity in patients without diabetes. Further larger-scale studies are needed to confirm our findings.
Abstract 10149: Clinical Predictors of Medical Therapy-Induced Improvement in Left Ventricular Function in Patients Diagnosed With Heart Failure With Reduced Ejection Fraction (HFrEF): The Intermountain Healthcare Experience
Authors: Joseph B Muhlestein, Heidi T May, Tami L Bair, Stacey Knight, Viet T Le, Benjamin D Horne, Kirk U Knowlton, Jeffrey L Anderson
Journal: Circulation (2022)

Introduction: When patients (pts) are diagnosed with HFrEF, it is hoped that medical therapy will improve their left ventricular ejection fraction (LVEF). However, which baseline clinical characteristics may predict an improvement in LVEF after medical treatment remains unclear. Methods: Pts with a baseline LVEF ≤35% and a follow-up LVEF ≥180 days later were categorized according to the change in LVEF identified between the baseline and follow-up LVEF’s (Increased [ΔLVEF ≥+10%]; No change [ΔLVEF=-9% to +9%]; Decreased [ΔLVEF ≥-10%]). Baseline characteristics and follow-up death rates were collected. Independent predictors of an improved LVEF were determined by logistic regression. Results: Qualifying HFrEF pts totaled 5,632 and were categorized by ΔLVEF as follows: Increased = 3,074 (54.6%); No change = 2,193 (38.9%); Decreased = 365 (6.5%). Baseline characteristics and independent predictors of an increase in LVEF are shown in the figure. During a median follow-up of 6.2 years, the death rate was 35.3%, 60.0%, and 72.6% (p&lt;0.0001) in patients with an increase, no change, or decrease in LVEF, respectively. Conclusions: In patients diagnosed with HFrEF and initiated on medical therapy, an increase in LVEF predicted a lower death rate. The strongest predictors of an increase in LVEF included female gender, the absence of ASCVD, a low initial BNP, a narrow QRS duration, and the presence of atrial fibrillation, pulmonary hypertension, and statin use. Explanations for these findings remain to be determined.
Abstract 10620: CD271 Expression Enhances Angiogenic Capacity in Human Adipose-Derived Stem Cells
Authors: Daiki Hashimuko, Oto Inoue, Soichiro Usui, Ayano Nomura, Kosei Yamaguchi, Yusuke Takeda, Chiaki Goten, Shinichiro Takashima, Kenji Sakata, Kenji Iino, Hirofumi Takemura, Masayuki Takamura
Journal: Circulation (2022)

Introduction: Therapeutic angiogenesis using stem cell transplantation can be a novel strategy for ischemic disease. Recently, stem cells with gene modifications have been considered as an option to boost therapeutic efficacy. Surface receptor CD271 has emerged as a useful marker for proliferative or angiogenic cell isolation from human organs. We hypothesized CD271 expression on adipose-derived stem cells (ADSCs) would increase their angiogenic capacity. Purpose: We aimed to assess in vitro and in vivo angiogenic capacity of CD271-over expressed human ADSCs. Methods: ADSCs were established from human adipose tissue from healthy subjects and transfected with lentiviral vector for CD271 overexpression (OE-ADSCs). Vector transfection was performed with previously reported method using protamine. Vector without CD271 gene insert was used to prepare control (Cont-ADSCs, Fig.A ). Overexpression of CD271 was evaluated by qPCR and flow cytometry after cell selection using puromycin. For in vivo angiogenic capacity, ADSCs were prelabeled with PKH26 living cell dye, injected via intra-muscular injection into mice subjected to limb ischemia model, and evaluated by immunohistochemistry of ischemic limb (gastrocnemius). Results: We found that mRNA expression of CD271 was 10,000-fold higher in OE-ADSCs than in Cont-ADSCs. Consistently, over 90% of OE-ADSCs expressed CD271 protein. ( Fig.B ). Overexpression of CD271 on ADSCs increased mRNA expression of angiogenic factors such as VEGFA and CXCL12 . Furthermore, mRNA expression of TIMP2, anti-angiogenic factor, was significantly decreased in OE-ADSCs ( Fig.C ). In cell therapy, we demonstrated that administration of OE-ADSCs enhanced in vivo angiogenic capacity evaluated by capillary density. Notably, ADSC engraftment capacity was also augmented in OE-ADSCs ( Fig.D ). Conclusion: These findings highlight the important role of CD271 expression on ADSCs for their angiogenic gene profile and cell therapy effects.
Abstract 10822: Familial Hypercholesterolemia in the EMERGE Network: 1-Year Outcomes After Return of Results
Authors: Alborz Sherafati, Ozan Dikilitas, Seyedmohammad Saadatagah, Benjamin Satterfield, David Kochan, Laney Jones, Emma Perez, Katherine Anderson, Zachary Salvati, Scott Hebbring, Richard Sharp, Amy Sturm, Richard Gibbs, Jodell Linder, Hana Zouk, Eric Venner, Wendy Chung, Josh Peterson, Gail Jarvik, Heidi Rehm, Dan M Roden, Marc Williams, Teri A Manolio, Iftikhar J Kullo
Journal: Circulation (2022)

Introduction: Relatively little is known about outcomes following return of secondary findings detected in large scale sequencing projects. We assessed 1-year outcomes following return of pathogenic/likely pathogenic (P/LP) variants associated with familial hypercholesterolemia (FH) in phase III of the eMERGE network (2015-2019). Methods: Adult participants (n=18,544) at 7 sites were enrolled in a prospective cohort study to study the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . Process, intermediate, and/or clinical outcomes within 1-year after return of results (RoR) were ascertained by electronic health record (EHR) review. A process outcome was defined as referral to a specialist or ordering new tests, including lipid profile and screening tests for coronary heart disease. An intermediate outcome was defined as new diagnosis of FH or atherosclerotic cardiovascular disease. A clinical outcome was defined as initiation or change in lipid-lowering medication. The primary outcomes were a new diagnosis of FH and modification of lipid lowering therapy. Results: Results were returned to 134 individuals, and data for 119 participants were available for the outcomes analysis. Process (86%), intermediate (49%), and/or clinical (26%) outcomes occurred in 92% of participants. Process outcomes included 72% with new tests ordered and 61% referred to a specialist. Before RoR, 86.5% of individuals with FH associated P/LP variants had a diagnosis of hypercholesterolemia but only 17.6% had a diagnosis of FH; 89% were on a statin but only 58% were on a high intensity statin. Following RoR, 44% (52/119) received a new diagnosis of FH. Lipid lowering treatment was modified in 26% (31/119), including initiation of a statin in 5%, increasing statin dose in 13%, and adding ezetimibe or a PCSK9 inhibitor in 12.6%. Conclusions: In a multisite cohort of EHR-linked biobanks, monogenic FH was underdiagnosed (only 17.6% had a specific diagnosis) and undertreated (only 58% were on a high intensity statin); 44% of participants received a new diagnosis of FH and 26% had lipid lowering treatment modified after RoR. These results highlight the clinical utility of returning FH variants in EHR-linked biobanks.
Abstract 10378: Metabolomic Signatures of Myocardial Glucose Uptake on FDG-PET
Authors: Mahesh K Vidula, Daniel P Kelly, Zoltan Arany, Kenneth B Margulies, Svati H Shah, Chris Petucci, Tom Cappola, Paco E Bravo, Senthil Selvaraj
Journal: Circulation (2022)

Introduction: FDG-PET is critical for evaluating myocardial inflammation, but requires preparation with a ketogenic diet (KD) to suppress physiologic myocardial glucose uptake (MGU). Even in monitored settings, incomplete suppression occurs in ~20% and remains the Achilles’ heel of the KD technique. We recently found in a crossover trial (NCT04275453; KEETO-CROSS) that despite achieving robust ketosis, ketone ester (KE) drink was inferior to KD to suppress MGU. We sought to understand whether a common metabolite signature might predict myocardial glucose suppression (MGS) irrespective of technique to ensure adequate myocardial preparation. Methods: Twenty healthy participants were first randomly assigned to acute KE ingestion or KD (24/72 hour visits) with subsequent crossover. Targeted plasma metabolomic profiling of 61 metabolites was performed at these 3 visits paired with FDG-PET. The association between metabolites and MGU was assessed using mixed effects linear regression. Results: The mean age of the participants was 30±7 years (50% women and 45% non-white). The Figure shows volcano plots for the relationship between metabolites and MGU. In both arms, two C4-OH carnitine species (markers of ketone/fatty acid oxidation) were strongly and inversely associated with MGU. Both species (C4-OH isobutyrylcarnitine and C4-OH butyrylcarnitine) were predictive of MGS in all patients (c-statistic 0.83, 95% CI 0.65-1.00 and 0.81, 95% CI 0.70-0.92, respectively) and much stronger than ketone/fatty acid levels. C4-OH isobutyrylcarnitine levels were higher during 24/72 hour KD visits than KE (p=0.018 and p=0.003). Conclusions: Metabolite markers of ketone and fatty acid oxidation strongly predict MGS, have robust discriminatory value, and may be used upstream of FDG-PET to reduce false positive scans. Strategies to enhance ketone/fatty acid oxidation (rather than circulating ketone/fatty acid levels) may improve MGS.